Toward a topological model of the NCX1 exchanger

The Na(+)/Ca(2+) exchanger (NCX1) catalyzes the counter-transport of sodium and calcium ions. Understanding how this is accomplished requires knowledge of the structure of NCX1 and identifying amino acid residues involved in binding and transport of ions. The amino acid sequence of NCX1 has been known for more than a decade. Based on hydropathy analysis, NCX1 was modeled to contain 12 transmembrane segments. In this model, the alpha-repeat regions, which are the result of a gene duplication event (see below), are oriented on the extracellular face of NCX1. In the years since NCX1 was sequenced, a considerable amount of effort has gone into testing the initial 12-transmembrane-segment model. Immunologic and protein-processing studies as well as functional analyses of mutants have determined the location of the amino and carboxy termini and several intracellular regions. However, disulfide bond analysis and cysteine mutagenesis coupled with accessibility studies indicate that the structure of NCX1 diverges from a simple membrane protein consisting only of transmembrane alpha-helical segments. These recent data support a model containing 9 transmembrane alpha-helices with the alpha-repeat regions forming nonhelical re-entrant loops. A bacterial protein containing a pair of alpha-repeat regions but of unknown function has also been shown to have oppositely oriented alpha-repeats.